Financial burden associated with discordance to intravenous iron therapies in US patients with iron deficiency anemia

BACKGROUND: Iron deficiency anemia (IDA) affects approximately 5 million people in the United States and has a significant impact on human health. Intravenous (IV) iron is indicated for treatment of IDA when oral iron is not effective or not tolerated. Several IV iron products are available, including oldergeneration and newer-generation products. Newer agents have certain benefits, including the ability to administer high iron doses in fewer infusions; despite the benefits, some payors require failure on older iron products before use of newer iron products in prior authorization processes. IV iron replacement regimens requiring multiple infusions may lead to patients not receiving recommended IV iron treatment per label; potential costs of this discordance may outweigh the difference in price between the older and newer products. OBJECTIVE: To quantify the burden of discordance to IV iron therapy and associated economic consequences. METHODS: This is a retrospective study using administrative claims data between January 2016 and December 2019 from adult patients who are enrolled in a commercial insurance program with a regional health plan. A course of IV iron therapy is defined as all infusions that occur within 6 weeks of the initial infusion. Discordance to therapy is defined as having received less than 1,000 mg of iron over a course of therapy. RESULTS: There were 24,736 patients included in the study. Baseline demographics were similar between the patients who received older- vs newer-generation products and patients who were concordant vs discordant. Discordance to IV iron therapy overall was 33%. Patients who received newer-generation products were less discordant to therapy (16%) than patients who received older-generation products (55%). In general, patients who received newer-generation products had a lower total cost of care than patients who received older-generation products. CONCLUSIONS: Discordance to the older-generation products was significantly higher than that to the newer-generation products. Patients who were concordant to therapy and on a newer-generation product had the lowest total cost of care, suggesting that overall cost of care is not necessarily proportional to the purchase price of the chosen IV iron replacement therapy. Optimizing concordance to IV iron therapy may lead to lower total cost of care in the IDA population.

RESULTS: There were 24,736 patients included in the study. Baseline demographics were similar between the patients who received older-vs newer-generation products and patients who were concordant vs discordant. Discordance to IV iron therapy overall was 33%. Patients who received newergeneration products were less discordant to therapy (16%) than patients who received older-generation products (55%). In general, patients who received newer-generation products had a lower total cost of care than patients who received older-generation products.

Plain language summary
Low body iron can cause iron deficiency anemia that is sometimes treated with intravenous (IV) iron. Most insurance companies think new drugs are more expensive. We compared total costs of IV irons grouped by old and new. We also looked at the costs of getting less than the suggested dose in 24,736 patients over 4 years. New irons had lower overall total costs than older irons.

Implications for managed care pharmacy
This study using claims data of approximately 25,000 patients demonstrated lower discordance to treatment and lower overall cost of care to newer-generation IV iron products. Prescriber education on financial implications of IV iron products and patient concordance to the recommended reference dose for IV iron (1,000 mg) is warranted. Policy preference toward concordance to IV iron treatment may lead to lower total cost of care in the iron deficiency anemia population.

Financial burden with intravenous iron therapies in US patients with iron deficiency anemia
Despite the decreased administration burden of newer-generation products, some payors require failure (inadequate therapeutic response, contraindication, or intolerance) on older-generation IV iron products before use of newer-generation IV iron products in prior authorization processes. [19][20][21][22][23] These restrictive policies solely focus on the IV iron drug acquisition costs, which are generally higher with newer-generation products, while overall total cost of care remains overlooked for this patient population. 24 This analysis specifically aimed to evaluate the impact of discordance by IV iron generation (older vs newer generation) on total cost of care.

Methods
This retrospective study used real-world medical and pharmacy administrative claims from multiple commercial regional plans. Data were derived from Magellan Rx Management's administrative claims databases. Claims incurred between January 2016 and December 2019 were included in the analysis. Data from 2020 were not included owing to the confounding effect of the COVID-19 pandemic.
A course of IV iron therapy was defined as an initial infusion plus all infusions that occur within 6 weeks of the initial. The US prescribing information (label) for a full treatment course for IV iron products can range up to 14 days; a total duration of 6 weeks was chosen to account for potential scheduling issues that arise in the real-world setting. [9][10][11][13][14][15] Additionally, the labels for all IV iron products refer to 1,000 mg as an acceptable dose for a course of IV iron treatment for IDA. Discordance to therapy was defined as having received less than 1,000 mg of iron over 6 weeks. On-label vs off-label use was out of the scope of the study.
The index date was defined as the first date of IV iron therapy initiation. The baseline period was defined as the 12 months prior to the index date, and the follow-up period was defined as the 12 months following the index date, inclusive ( Figure 1). Patients were required to be aged at least 18 years on the index date as well as have an International Classification of Diseases, Tenth Revision diagnosis code for IDA in the baseline period. All patients were continuously enrolled in medical and pharmacy benefits for at least 12 months prior to and following the index date. Patients with a claim for hemodialysis at any point were excluded.
Various cohorts were developed to compare all-cause cost and use between different patient groups. A group of board-certified hematologists and pharmacists were consulted during the development of the protocol to ensure the cohorts and discordance were appropriately defined based on clinical practice.

CONCLUSIONS:
Discordance to the older-generation products was significantly higher than that to the newer-generation products. Patients who were concordant to therapy and on a newer-generation product had the lowest total cost of care, suggesting that overall cost of care is not necessarily proportional to the purchase price of the chosen IV iron replacement therapy. Optimizing concordance to IV iron therapy may lead to lower total cost of care in the IDA population.
Anemia is a common health condition in which the number of red blood cells and/or hemoglobin concentration within them is lower than normal. 1 An estimated average of 5.6% of the US population meets the criteria for anemia. 2 A higher prevalence of anemia is associated with certain comorbidities, and the economic burden of anemia varies depending on those comorbidities. [3][4][5] For example, the mean economic burden attributable to anemia ranges from $7,092 in those with comorbid rheumatoid arthritis to $29,500 in those with comorbid congestive heart failure (HF). 5 A common cause of anemia is iron deficiency, which occurs when stored iron is reduced. 1,4 This type of anemia is known as iron deficiency anemia (IDA) and affects approximately 5 million people in the United States. 4,6 Intravenous (IV) iron is indicated for treatment of IDA when oral iron is not effective or not tolerated. 7 IV iron products are iron complexes consisting of a core of iron surrounded by a carbohydrate shell; newer formulations have larger, more complex carbohydrate shells or matrix structures with more stability. 7,8 Therefore, IV iron products can be grouped as older-and newer-generation products. Older-generation products are formulated to be infused at lower doses (< 500 mg); these products are approved for administration in more than 2 infusions (iron sucrose, iron dextran, and sodium ferric gluconate) and may require a test dose. [8][9][10][11] Due to the lack of controlled release with oldergeneration products, infusion of a higher dose (eg, 1,000 mg) requires longer chair times (4 to 6 hours). [10][11][12] Newergeneration products are formulated to allow for infusion of higher doses (≥ 500 mg) over 15 to 60 minutes and include ferric derisomaltose as 1 infusion, ferric carboxymaltose as 2 infusions recommended, and ferumoxytol as 2 infusions. 8,[13][14][15] Products differ in terms of the maximum amount of iron that can be safely administered in a single infusion.
US Food and Drug Administration-approved IV iron products with treatment courses requiring 2 or more IV infusions may be associated with suboptimal adherence. 16 Multiple IV infusions impose a burden on patients; this may result in discordance between the actual IV iron dose given and the required/prescribed dose, which is generally at least 1,000 mg for patients not receiving hemodialysis. 17,18 Consequently, there may be a cost associated with this discordance.

Financial burden with intravenous iron therapies in US patients with iron deficiency anemia
cohort received iron sucrose as the index drug (59.3%), followed by iron dextran (29.8%) and sodium ferric gluconate (10.9%). In the newer-generation-product cohort, 69.9% of patients received ferric carboxymaltose at index and 30.1% received ferumoxytol ( Table 1).
The Deyo-Charlson Comorbidity Index was similar for the concordant and discordant groups ( Table 2).
Discordance to IV iron therapy was approximately 32.5% overall (Table 3). Patients on older-generation products were more discordant to their IV iron treatment than patients on newer-generation products (54.8% vs 15.9%, respectively) (Table 3).
Overall, patients with IDA had a total cost of care of $36,552. Patients on newer-generation products had lower overall mean total cost of care when compared with all patients on older-generation products ($35,353 vs $38,164, respectively) ( Table 4). Specifically, patients on newer-generation products had lower outpatient hospital costs than patients on older-generation products ($13,654 vs $18,385, respectively). Furthermore, patients who were discordant to any IV iron treatment had a higher mean total cost of care compared with patients who were concordant to any IV iron treatment ($41,050 vs $34,387, respectively) ( Table 4). When compared with concordant patients, discordant patients had higher mean inpatient hospital ($18,212 vs $14,449) and outpatient hospital costs ($33,736 vs $29,654).
The lowest-cost patients included in the study were those who were concordant to newer-generation iron products, whereas the highest cost was seen in patients discordant to newer-generation products (Table 4).
Descriptive analyses were performed for all variables of interest. Discrete (count) variables are presented by counts and percentages. Continuous variables are presented as means and SDs unless otherwise noted. Statistical methods used in this study include chi-square tests for categorical variables and t-tests for comparisons of continuous variables among cohorts.
Generalized linear models and logistic regression were used to help minimize the effects of confounders on outcomes of interest and account for differences in the population demographic and clinical characteristics.
All study data were compliant with the US patient confidentiality requirements, including the Health Insurance Portability and Accountability Act (HIPAA) of 1996 regulations and Health Information Technology for Economic and Clinical Health (HITECH) Act of 2009. Because all databases used in the study were fully deidentified and compliant with HIPAA/HITECH, this study did not require institutional review board approval.

Results
A total of 24,736 patients were included in this study; 10,546 (43%) received older-generation products and 14,190 (57%) received newer-generation products. The mean age in both cohorts was approximately 46 years, and 85% of patients in each cohort were female (Table 1).
There was no difference in the comorbidity indices of the groups receiving newer-and older-generation products, respectively. Most patients in the older-generation-product

FIGURE 1
Study Period

Discussion
Prior to this study, there was a paucity of total cost of care data for IDA. The average total cost of care per patient with IDA is $36,552; that is approximately 7 times the average spending of commercially insured patients. 25 The total cost of care of patients with IDA receiving older-generation IV iron products was higher than the average cost of care. This was highly associated with discordance to IV iron therapy, as patients receiving older-generation products were much more likely to be discordant (54.8%) than those treated with newer-generation products (15.9%). In this study, 5 settings of care were evaluated: outpatient office, outpatient hospital, inpatient hospital, emergency department, and ambulatory pharmacy. For discordant patients, the cost of care was slightly higher in each of the settings of care; however, specific drivers of cost were not apparent. The total cost of care remained significantly higher using older-generation products compared with newer-generation products, when accounting for comorbidities and other covariates.
Underdosing treatment of IDA has important therapeutic and, in some cases, serious clinical consequences; however, data in this area are limited. 26,27 A retrospective study of 459 patients with or without anemia who received a higher cumulative dose of ferric carboxymaltose (501 mg to 1,000 mg) showed greater hematologic efficacy than a lower dose (500 mg); patients who received a higher dose of ferric carboxymaltose had significantly lower odds of clinical failure compared with patients who received a dose of 500 mg (odds ratio = 0.36; 95% CI = 0.12-0.92). 26 In the largest hard-endpoint IV iron trial to date, 2,141 patients with chronic kidney disease receiving hemodialysis were randomized to either a low-dose or high-dose IV iron regimen. 27 Compared with the low-dose arm, patients in the high-dose treatment arm were less likely to have a fatal or nonfatal myocardial infarction or to be hospitalized for HF than those who received the low-dose regimen. Although not directly linked to the population considered in this study, in which patients receiving hemodialysis were excluded, these data provide a glimpse of potential clinical consequences of undertreatment with IV iron. The totality of epidemiological data and clinical trial experience point to a significant health burden of underdosing treatment of IDA, which provides a biological basis for understanding why underdosed or discordant treatment of patients eligible for IV iron is associated with increased total cost of care.
These data further support the analysis by La Vallee et al published earlier this year using medical and pharmacy claims and electronic health records from more than 300 million patients. 28 The authors found similar results

MODELING
Total Cost of Care Modeling. When adjusting for covariates, total cost of care was still significantly lower for patients on newer-generation products ($31,854) compared with patients on older-generation products ($33,991). Discordance to IV iron therapy increased the total cost of care by $5,160 compared with concordant patients (P < 0.01).
Concordance Modeling. A logistic regression model evaluating concordance against demographics and comorbidities of interest as well as whether patients were on older-generation or newer-generation products showed that patients with celiac disease, Crohn's disease, or colon cancer and those who were pregnant were less likely to be concordant. Overall, patients on older-generation products were approximately 6.5 times more likely to be discordant to therapy than those on newer-generation products. Although statistically significant, the listed comorbidities had little practical impact on discordance.  Newer-generation IV iron products were associated with reduced total cost of care for treating patients with IDA compared with older-generation products despite the higher average sales price. This study offers new data to inform payor policy decision-making processes suggesting that restricting use of newer IV irons by step edits through the older low-dose IV irons ultimately results in increased costs.
IV irons have distinct product properties, making simple therapeutic exchange often inappropriate. Furthermore, safety profiles vary between products with respect to hypersensitivity reactions, hypophosphatemia and osteomalacia/fractures, and/or cardiovascular outcomes. 7 These factors may drive total cost of care differences between the various IV iron treatments.
The study also identifies concordance to therapy (1,000 mg within 6 weeks) as an important factor to further reduce total cost of care. Concordance could be increased by strengthening focus on patient compliance and by eliminating the burden of multiple infusions. Study results are strengthened by the fact that off-label use, such as older-generation products given at higher doses in fewer infusions, is not excluded; rather, it is the total cumulative 6-week dose that is important. Finally, because this study period occurred prior to 2020 and ferric derisomaltose was not included, additional research on the effect of a single-dose infusion of 1,000 mg on concordance and total cost of care is warranted to corroborate the findings of this study.

LIMITATIONS
This study was conducted based on data from commercial regional health plans and may not be generalizable to other types of programs including Medicaid and Medicare. Total cost of care only included products and services billed to a health plan via administrative claims data.
Previous literature has distinguished older vs newer IV iron products, and these classes were carried over to this study with additional context to formulation and dosing that further separates these products by generation. 7,8,12 On-label vs off-label use was not considered as part of this evaluation; rather, the metric of total dose in 6 weeks was accounted for.
The recommended total treatment dose of 1,000 mg was based on the 6 product labels and, because electronic medical record data were not tied to claims data, did not reflect individual iron need. It is possible that, based on patient weight and hemoglobin, the total iron need and therefore the prescribed dose for some patients could have been less than 1,000 mg.

Conclusions
Despite older-generation IV iron products having lower drug average sales price than newer-generation IV irons, the newer-generation products are associated with a significant reduction in total cost of care. These cost savings are largely driven by a reduction in discordance to therapy with newer-generation products. Even with the newer-generation products for which 2 infusions are required or recommended as per the label, some discordance to therapy remains; IV iron administered in a single high-dose infusion may eliminate discordance with potential to reduce total cost of care.

DISCLOSURES
Magellan Rx Management received funding for this study from Pharmacosmos Therapeutics Inc. AESARA contributed to study design and data analysis. Magellan Rx Management contributed to the study design, data analysis, and interpretation of results. Pharmacosmos Therapeutics Inc. participated in the study design and interpretation of results.